JP2002522111A - Improved method of targeted local treatment of disease - Google Patents

Abstract

(57) Abstract: A method and apparatus for local treatment of diseased tissue, comprising local or systemic application of a PDT agent to diseased tissue followed by local application of light.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present application is filed with US Ser. No. (USSN) 0 filed on Oct. 30, 1996.
This is a continuation-in-part application of 8 / 738,801.

TECHNICAL FIELD [0002] The present invention relates to methods and devices for the local treatment of tissues, particularly diseased tissues, using photodynamic therapy (PDT) and PDT agents. More specifically, the present invention relates to methods and devices for the local or systemic use of PDT agents on diseased tissue, as well as the local use of light on diseased tissue.

BACKGROUND OF THE INVENTION PDT is used to treat cancer and other diseases that limit the invasiveness of therapeutic interventions and ensure that the likelihood of collateral damage to healthy non-diseased tissue is reduced. Developed in Important elements of PDT include either selective application or selective uptake of the photoactive agent into diseased tissue, and site-directed application of activating light. The PDT agent is typically applied systemically (eg, via intravenous injection or oral administration) or topically applied directly to the diseased tissue (eg, via a topical cream, ointment, or spray). After administration of the drug (typically 30 minutes to 72 hours), an activating light is applied to the diseased site to activate the drug locally and destroy diseased tissue. Light is applied by direct illumination of the site, or by delivering light energy to an internal location using a fiber catheter or similar means.

[0004] Modern PDT treatment modalities are based on systemic application of porphyrin-based drugs or local or systemic application of psoralen-based drugs. Examples of porphyrin-based drug, porfimer sodium (PHOTOFRIN (R)), hematoporphyrin derivative (HPD), or SNET ₂ and the like. PHOTOFRIN (
Is one of several drugs currently approved by the FDA. Porphyrin-based drugs are generally derived from complex mixtures of naturally or synthetically prepared substances. Many components of porphyrin-based drugs are lipophilic. As a result of this lipophilicity, porphyrin-based drugs have been shown to have a slight tendency to accumulate preferentially in some tumors. However, the targeting of such agents to diseased tissue is still unacceptably low when compared to uptake in healthy tissue (ie, uptake in diseased tissue over healthy tissue is 2-10 fold). In addition, porphyrin-based drugs have been developed primarily as a result of the desire to obtain drugs that are equivalent to highly transmitted activating light to allow treatment of deeply located cancerous tumors. For example, porphyrin-based drugs are typically activated using light at a wavelength between 600 and 750 nm, which can penetrate tissues 1 cm or more deep. In contrast, light at wavelengths below 600 nm will only penetrate tissue that is much less than 1 cm deep.

[0005] However, the dark toxicity of most porphyrin-based drugs is high. Dark toxicity is cytotoxicity in the absence of activating light. Only a slight increase in cytotoxicity is achieved upon irradiation, which requires high doses of the drug to effect treatment in a particular tissue.
In addition, the systemic clearance time, which is the duration of drug administration when significant drug concentrations are present in the skin and other external tissues, can be extended by weeks or months, and patients may experience severe skin irritation or other It is necessary to avoid exposure to bright light or sunlight for an extended period to avoid complications. For systemic administration, 30 minutes between drug administration and photoactivation.
A delay of minutes to 72 hours is also required, essentially hampering the possibility of immediate treatment of such diseased tissue upon its discovery. Further, the discovery and treatment of gastrointestinal disorders, such as Barrett's esophagus, requires at least two endoscopic methods. That is, a method of diagnosis and a subsequent method of treating diseased tissue with light after administration of a PDT drug.

[0006] The absence of a significant difference between light and dark cytotoxicity and low preferential concentration ratios of the most common PDT drugs requires high drug doses. For example, the dosage for treatment of adult males with PHOTOFRIN® requires over 100 mg of drug at a price of over $ 5000 for the drug alone. This large dose also increases the significant likelihood of adverse side effects (such as cutaneous phototoxicity) in healthy tissues that can persist for weeks. Also, porphyrin-based drugs have wavelengths above 600 nm (ie,
Because of activation with light in the near-infrared light (NIR), porphyrin + NIR-based methods may also expose patients to a significant risk of serious complications due to tissue penetration of such NIR light. Complications include perforation of internal structures, such as the esophagus during treatment of esophageal disease, due to undesired activation of drugs present in healthy tissue layers outside the zone of the local treatment site.

Further, porphyrin-based PDT agents, typically activates a photoactivatable cellular characteristics through the type II mechanism is a transformation of the cells O ₂ into cytotoxic singlet oxygen. Because cellular O ₂ levels are prone to depletion upon activation of type II PDT agents, the use of such agents requires relatively low intensity of irradiation and relatively low intensity to maintain O ₂ levels well over the duration of photoactivation. Requires a relatively long irradiation time. For example, PHO
In the treatment of Barrett's esophagus with TOFRIN®, the light intensity typically needs to be less than 100-150 mW / cm ² at the time of treatment and requires more than 10-20 minutes of irradiation. Numerous practitioners, the type II drug, it avoids the tissue treatment that may impair the blood circulation at the treatment site during irradiation, and that in order to avoid potential lack of available O ₂ is equally important Also headlines. For this reason, careful adjustment of the illumination device and method is important to ensure that the illumination of the appropriate light intensity is delivered without affecting the tissue in a manner that affects blood circulation.

[0008] Barrett's esophagus is difficult to access via conventional surgical means,
Because it occurs in a location that is easily accessible using an endoscopic catheter, PDT
Is a complete example of superficial disease that is an attractive candidate. This is a condition in which chronic acid reflux from the stomach stimulates the esophagus at the gastroesophageal junction, causing epithelial tissue in the esophagus to proliferate. Patients with Barrett's esophagus have a significantly increased risk of developing esophageal cancer. FDA uses PDT (PHOTOF by light at 630 nm) to disrupt tissue growth in Barrett patients
RIN®) was approved. A similar treatment modality can be used to remove esophageal strictures caused by esophageal cancer.

A general method of treating Barrett's esophagus with PDT is shown in cross section in FIG. Esophagus 10 has a proximal tissue surface 12 and a distal tissue surface 14. In the example shown in FIG. 1 (а), the portion of the esophagus 10 is a healthy tissue 16,
Another part is diseased tissue 18. Typically, a non-cooperative balloon 20 inserted into the esophagus 10 is used to stabilize the tissue to be treated. The balloon is filled with a gas or liquid and expands to a known radius (almost filling the esophagus) while avoiding esophageal inflation. Expansion of the can lead to restriction of blood flow to the treatment site impairing O ₂ supplied during photoactivation. An optical fiber inserted into the center of the balloon 20 is used as a light source 22 to obtain a uniform light intensity on the surface of the balloon. This balloon 20
The outer structure of may be composed of a substance that scatters the activating light 24, or may be transparent to the activating light.

Thereby, the PDT drug present on the tissue located on the proximal side of the balloon (on the proximal tissue surface 12) is activated by the light emitted from the surface of the balloon 20. Because the balloon 20 is non-cooperative, it is possible to estimate the light intensity at the surface of the balloon based on knowledge of the balloon's geometric properties and the light emission properties of the light source 22. The diffusion tip of an optical fiber is an example of such a light source. However, since the outer surface of the balloon 20 generally does not exactly conform to the shape of the esophagus, the proximal tissue surface 12
It is not possible to accurately estimate the light intensity at every point along the perimeter of. Furthermore, if the light field present at the proximal tissue surface 12 is not uniform, for example due to the non-uniform light emission characteristics of the light source 22 or the incorrect position of the light source 22 in the esophagus 10, this may result in uneven treatment. There is. In extreme cases, such uneven treatment can cause sufficient tissue damage, resulting in tissue perforation and patient death.

As shown in FIG. 1 (b), activation of the PDT drug in the esophagus upon irradiation creates a treatment zone 26, which generally creates the entire zone of diseased tissue in FIG. And may extend radially and circumferentially far beyond the edge of the zone of diseased tissue 18. In fact, the use of NIR light for drug activation creates a treatment zone that extends a significant distance from the proximal tissue surface 12 of the esophagus 10 to the distal tissue surface 14. This is a result of the large depth of penetration that is characteristic of NIR light and the presence of significant systemic concentrations of the drug in healthy tissue. In extreme cases, the expansion of the treatment zone can damage enough healthy tissue, resulting in tissue perforation and death of the patient.

[0012] This example of the use of PDT for the treatment of superficial lesions highlights the numerous shortcomings of current methods and devices.
Points are shown. For example: (1) systemic drug application is expensive due to high drug dosage requirements; (2) systemic drug application results in sensitization of healthy tissue outside the desired treatment zone
(3) Systemic drug application results in prolongation of skin photosensitization; (4) Systemic drug application applies drug to diseased tissue while excluding surrounding healthy tissue.
Delivery requires a large delay between disease diagnosis and disease treatment; (5) Systemic drug application requires the PDT practitioner to
(6) systemic drug application may be uneven due to uneven distribution of drug to diseased tissue.
(7) The use of type II drugs is₂Slow and prolonged drug activation to avoid deficiency
(8) The use of type II drugs limits blood flow and consequent O ₂ Requires careful tissue handling to avoid deficiency; (9) the use of type II drugs, when combined with NIR-activated light, generally
Excessive treatment depth in local topical application and adverse effects on surrounding healthy tissue
Effect. Therefore, it is an object of the present invention to increase the efficacy and safety of treatment and to reduce
Provide new methods and apparatus for improved application of PDT while reducing usage
It is to be.

SUMMARY OF THE INVENTION [0013] The present invention relates to methods and devices for local treatment of diseased tissue, including local or systemic application of a PDT drug to diseased tissue, followed by local application of light. In general, this method uses P
Applying the DT agent to the diseased tissue to form a treatment zone, removing excess drug, and applying light to the treatment zone to activate an agent associated with the diseased tissue. Light is transmitted through the treatment zone with minimal activation of the drug outside the treatment zone.

[0014] In a preferred embodiment, Rose Bengal is the PDT drug. In another embodiment, the PDT agent is applied directly to the treatment zone only. Alternatively, PDT can be applied systemically. In yet another embodiment, the depth of activation of the PDT drug is adjusted by appropriate selection of the wavelength of the activating light to avoid activation of the drug that may be located in the underlying healthy tissue. Can be. In yet another embodiment, the diseased tissue is diagnosed before applying the PDT drug. In another example, the discovery and treatment of a lesion can be performed in a short period of time using a single method (such as an endoscope) regardless of the method of isolation diagnosis and treatment. In another embodiment, the rate of treatment is not limited by an oxygen-dependent mechanism. In another embodiment, the activating light is delivered by a "balloon" or other delivery device located at the disease site. In another embodiment, the methods of the present invention can be used to treat diseases in the gastrointestinal tract.

[0015] The methods of the present invention can be used to treat diseases in the blood vessels of the circulatory system. The invention also relates to a device for local treatment of diseased tissue. Accordingly, the present invention relates to methods and devices for improving the uniformity of light delivery, as well as improving the safety and effectiveness of PDT for the treatment of Barrett's esophagus and other conditions and reducing its cost.

BEST MODE FOR CARRYING OUT THE INVENTION The method and device of the present invention provide improved treatment of various dermatological disorders such as psoriasis or skin cancer, and individual diseases in the body such as gastrointestinal or tracheal disorders. Applicable to diseased tissue at the site. The invention can also be used to treat other anatomical sites, including intraperitoneal, intraperitoneal, intracardiac, intracirculatory, intracerebral, and genital tract.

In general, the method of the present invention includes one or more of the following steps. Initially, the disease is diagnosed, for example, using histological examination, or by measuring the autofluorescent properties of the diseased tissue, or by detecting the selective uptake of an indicator drug, such as a fluorescent dye or a PDT drug, into such diseased tissue. You. Thereafter, a sufficient amount of a local or systemic composition of the desired PDT agent is applied to the disease site to cover, reflux, or saturate the diseased tissue. After a short accumulation period to coat and reflux or otherwise activate the drug within the diseased tissue, to remove or wash away excess drug from the diseased site and activate the drug associated with the diseased tissue, A substantially uniform light field is applied to the disease site.

For treatment of superficial diseased tissue, the wavelength of light is selected to allow light transmission to diseased tissue, but to minimize further light transmission over diseased tissue to underlying healthy tissue. Is preferably performed. For example, visible light in the spectral range of 400-600 nm can be used to provide a shallow penetration depth of about a few millimeters or less. The use of such light provides the efficacy of drug activation in superficially diseased tissue while at the same time minimizing the potential for harmful photosensitization of the underlying tissue. Preferably, laser light is used. Laser light is delivered by a fiber optic catheter.
Alternatively, the light is delivered by direct irradiation. Other alternative light source configurations and delivery devices include fiber optic bundles, hollow core optical waveguides, and liquid-filled waveguides. Other light sources include light emitting diodes, microlasers, monochromatic lasers,
Lamps for the generation of continuous laser or activating light, and continuous wave or pulsed lasers or lamps. Either single-photon excitation or two-photon excitation can be used for drug activation. A more detailed description of such an excitation method can be found in
Application No. 08/7 filed on Oct. 30, 996, and assigned to the present applicant.
39,801, which is incorporated herein by reference.

Further, the time and order of application of the drug and light may be varied. For example, the application of the drug and phototherapy regime may be repeated one or more times to remove residual diseased tissue. Further, for some applications, an increased delay between drug application and phototherapy may be advantageous. Also, the steps of applying the PDT drug almost immediately after the step of diagnosing, removing excess drug and applying light can be performed to perform the method of diagnosis and treatment in a single procedure. When diagnosing or detecting diseased tissue using PDT drug ingestion, a step of applying activation light is performed immediately after the step of diagnosis. Alternatively, they may be an indefinite delay between diagnosis and PDT treatment.

As a PDT or photosensitizer, it is inexpensive, non-toxic, proven safe for human use, has meaningful inherent lipophilicity, and exhibits type I and II reactions ,
Therefore, it can be activated by a type I, oxygen-dependent mechanism,
It is preferred to use Rose Bengel because it is strongly phototoxic when activated by light between nm and 600 nm. By its O ₂ dependent reaction, Rose Wenger is photoactivatable and compatible high strength, treatment time can be shortened thereby against the porphyrin-based agents. More specifically, Rose Wengel is sufficient for the activation of superficial diseases, substantially avoiding the potential for activation of underlying healthy tissue,
Activated optimally with light between 500 and 600 nm. Such PDT
An example is a solution of rose bengel prepared with a suitable lipophilic delivery vehicle such as l-octanol or liposomes.

Alternatively, other PDT agents, including Type I or Type II agents, can be used. Examples of such PDT agents include psoralen derivatives; porphyrins and hematoporphyrin derivatives; chlorin derivatives; phthalocyanine derivatives; rhodamine derivatives; coumarin derivatives; benzophenoxazine derivatives; , Merocyanine 540 (MC 540); vitamin D; 5-amino-levulinic acid (ALA); photosan; pheophorbide-а (Ph-а);
A variety of phenoxazine dyes were prepared from fukumphenoxazine Nile blue derivatives;
HOTOFRIN; benzoporphyrin derivative monoacid; SnET ₂ ; and lutex. The inventors of the present invention believe that all present and future PDT agents will work in the methods and devices of the present invention. Also, the invention is not limited to the use of PDT drugs. Alternatively, one or more PDT agents can be used during the treatment regime.

In another embodiment, the PDT used in the present invention can include at least one target component. Examples of such target components include DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complex drugs,
Lipid or complex drugs, protein or complex receptors, chelating agents, and encapsulating excipients. Such targeting moieties can be used to improve the selectivity of drug delivery to diseased tissues and can be coupled to a photosensitized PDT drug (eg, if the PDT drug is encapsulated in an excipient consisting of the target component). Sensitized) or photosensitized P
It can function either by being attached to a DT agent (eg, a PDT agent is covalently attached to a target moiety).

In another preferred embodiment, the PDT agent is applied directly to the diseased tissue. The use of direct topical application offers a number of advantages. In particular, this improves the target of the drug specific to diseased tissue and reduces the latency required between drug administration and photoactivation, thereby shortening the treatment cycle and reducing the The potential is substantially eliminated, drug consumption is reduced, and the overall likelihood of side effects from exposure to the drug is reduced. Preferably, the medicament is applied as a topical spray or lavage. After a brief accumulation period (typically not more than 30 minutes), excess drug is removed from the tissue surface by washing with a liquid such as water or saline. After this washing, the persistent drug associated with the diseased tissue is preferably activated by irradiation of the diseased site with visible light between 400 nm and 600 nm. Optically, light can be applied as described above. Alternatively, PDT can be applied systemically. For example, this application is possible via intravenous injection or parenteral administration (eg, by consumption of a tablet or liquid composition of the PDT drug). In another embodiment, heat may be applied to the treatment zone to increase the effectiveness of PDT via high heat. Heat can be applied, for example, by a superheated liquid in an irradiation balloon, a transparent heating pad positioned between the irradiation source and the tissue, or by simultaneous irradiation of the treatment site with infrared energy.

Some examples of these embodiments of the present application are shown in cross-section in FIGS. 2 (a) and 2 (c). FIG. 2A shows an example of treatment of a diseased esophagus using a non-cooperative balloon 20 irradiation device. First, the treatment zone 30 is identified. This can be done, for example, by endoscopy of the esophagus and macroscopic or spectroscopic confirmation of the diseased tissue zone. Such confirmations include detecting histological changes or other macroscopic indicators of the disease, detecting changes in autofluorescence, or detecting the uptake of PDT or other drugs into the diseased tissue. After confirmation of the treatment zone 30, the PDT drug is applied to the identified diseased tissue. The medicament can be applied, for example, by systemic application or more preferably by spraying using a nozzle or other means provided at the distal end of the endoscope. Thereafter, excess drug is removed from the site, for example, by natural systemic clearance or rinsing with a liquid.

Next, the transparent non-cooperative balloon device 20 is used to span the treatment zone 30.
Into the esophagus. The non-cooperative balloon 20 is filled with a gas or liquid to a predetermined pressure to establish a desired predefined radius. The visible light 24 is then uniformly delivered radially to the treatment site through the wall of the balloon 20 using a light source 22, such as a fiber optic compressor, positioned along the central axis of the balloon.

Also, the balloon 20 can be filled with a scattering medium, such as a diluent in lipids, to improve the uniformity of the light intensity delivered at the surface of the balloon. In addition, balloon 20 can be comprised of or include a substance that scatters light 24 delivered at the surface of the balloon to further improve the uniformity of light intensity delivered at the surface of the balloon. . Examples of such materials are naturally translucent materials such as latex; polymers containing particulate scattering material; or polymers with rough surfaces.

In the example shown in FIG. 2A, the intensity of the light source 22 is
At a pre-defined level for a pre-determined duration based on the fill radius of the and the desired light intensity and light intensity at the balloon surface. Another example of this embodiment is shown in cross-section in FIG. 2 (b), where diseased esophageal tissue is treated using an expanded non-cooperative balloon 40. In this example, after confirming the diseased tissue, the PDT drug is applied to the confirmed diseased tissue. Thereafter, excess drug is removed from the site.

Next, in order to span the treatment zone 30, the transparent non-cooperative balloon device 40
Into the esophagus. The uncooperative balloon 40 is filled with a gas or liquid to substantially dilate or slightly dilate the esophagus, providing a more uniform tissue surface 12 for irradiation by removing convolutions in the esophageal surface. I do. Measure the filling pressure to establish the radius of the filling balloon. The visible light 24 is then uniformly delivered radially to the treatment site through the wall of the balloon 20 using a light source 22, such as a fiber optic compressor, positioned along the central axis of the balloon.

The balloon 40 can also be filled with a scattering medium, such as a diluent in lipid, to improve the uniformity of the light intensity delivered at the surface of the balloon. In addition, balloon 40 can be comprised of or include a substance that scatters light 24 delivered at the surface of the balloon to further improve the uniformity of light intensity delivered at the surface of the balloon. . Examples of such materials are naturally translucent materials such as latex; polymers containing particulate scattering material; or polymers with rough surfaces.

The pressure used to fill the balloon is measured and used to establish the operational radius of the filling balloon, and the intensity of the light source 22 depends on the filling radius of the non-cooperative balloon 20 and the surface of the balloon. At a pre-defined level for a pre-defined duration based on the desired light intensity and light quantity. In this alternative embodiment, to avoid potential stenosis or other non-specific irritation of the esophageal tissue, to minimize convolution of the treated esophageal segment without greatly expanding the esophagus, Preferably, sufficient pressure is used. Yet another example of this embodiment is shown in cross section in FIG. 2 (c), where diseased esophageal tissue is treated using a cooperative balloon 50. In this example, after confirming the diseased tissue, the PDT drug is applied to the confirmed diseased tissue. Thereafter, excess drug is removed from the site.

Next, a transparent cooperative balloon device 50 is inserted into the esophagus to span the treatment zone 30. The cooperative balloon 50 is filled with a gas or liquid to substantially dilate or slightly dilate the esophagus, further removing the non-uniform contact between the esophageal surface and the balloon, for further irradiation. Provides a uniform tissue surface. Measure the filling pressure to approximate the radius of the filling balloon. Then, the balloon 50 using the light source 22, such as an optical fiber compressor, is disposed along the central axis of the balloon.
The visible light 24 is uniformly delivered to the treatment site in the radial direction through the wall of the patient.

The balloon 50 can also be filled with a scattering medium, such as a diluent in lipid, to improve the uniformity of the light intensity delivered at the surface of the balloon. Further, balloon 50 can be comprised of or include a substance that scatters light 24 delivered at the surface of the balloon to further improve the uniformity of light intensity delivered at the surface of the balloon. . Examples of such materials are naturally translucent materials such as latex; polymers containing particulate scattering material; or polymers with rough surfaces.

The pressure used to fill the balloon is measured and used to establish the operational radius of the filling balloon. Thus, in this example, the intensity of the light source 22 is manipulated at a level selected based on the operational radius of the filled cooperative balloon 50 to deliver the desired light intensity and the amount of light at the surface of the balloon. Is done. In this alternative embodiment, to minimize convolution of the treated esophageal segment without greatly expanding the esophagus (to avoid potential stenosis or other non-specific irritation of esophageal tissue) Preferably, sufficient pressure is used.

For the treatment of diseases in the blood vessels of the circulatory system (such as arterial or venous plaque), FIGS. 3 (a) and 3 (b) show another preferred embodiment of the present invention. In the specific example of FIG. 3 (a), the photosensitizing agent is applied parenterally or by intravenous injection. The drug accumulates in the diseased tissue of the vessel wall 60 to form a treatment zone 62. The drug is selected based on the preferential concentration in the disease substance present in the desired treatment zone. After a short accumulation period, light 6 is applied to the disease site to activate the drug associated with the disease substance.
4 applies. This application can be made using a fiber optic catheter 66 or similar means having a focusing, collimating, or diffusing terminal for spatial adjustment of light delivery. The fiber optic catheter 66 can deliver the light 64 directly to the treatment zone 62 and the light can be applied locally. To minimize light transmission through the underlying healthy tissue, it is preferable to use visible light in the spectral range of 400-600 nm to obtain a shallow penetration depth of about a few millimeters or less. The use of such light provides the efficacy of drug activation in superficially diseased tissue while at the same time minimizing the potential for harmful photosensitization of the underlying tissue.

Alternatively, as shown in FIG. 3 (b), a photosensitizing drug can be administered to the diseased substance in the treatment zone 62 via local direct application of the drug. Drug delivery is applied directly or near the treatment zone 62 to a drug delivery device 68 such as a capillary attached to a fiber optic catheter 66 that is used to deliver small quantities of drug as a stream 70 or other flow and ending near its end. Can be easily performed via Alternatively, the delivery device 68 can be separated from the fiber optic catheter 66, thereby facilitating independent locations of the respective ends of the light delivery fiber optic 66 and the drug delivery device 68. In any embodiment, the treatment zone 62
Delivery of a small amount of the photosensitizing agent to the diseased substance occurs in the above, and after a short accumulation period, light 62 is applied to the diseased site to activate the drug associated with the diseased substance.

In these examples, it is preferable to use rose bengel as a photosensitizing agent.
Rose Wengel is optimally activated using light between 500 nm and 600 nm which is sufficient for the activation of superficial disease substances and substantially avoids the possibility of activation of the underlying healthy tissue . In addition, the drug is compatible with high intensity photoactivation and can be used to substantially reduce the treatment time required for other drugs, such as Type II PDT drugs. This description is provided for the purpose of illustration only, and is not intended to limit the invention of the present application as defined in the following claims. What is newly claimed and desired to be protected by Letters Patent is set forth in the appended claims.

[Brief description of the drawings]

FIG. 1 (a) is a cross-sectional view of the esophagus showing a normal method for treating Barrett's esophagus using PDT, and (b) is a view showing a treatment zone of the method of (а).

FIG. 2 (a) shows an example of an embodiment of the present invention for treatment of diseased esophageal tissue;
(B) is a figure which shows another complementary example of the Example of (а), and (c) is a figure which shows another complementary example of the Example of (а).

FIG. 3 (a) shows an example of another embodiment for the treatment of a disease in a blood vessel of the circulatory system, and (b) shows an example in which the PDT drug is directly applied to the diseased tissue (a). FIG. 6 shows another example of an example.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/7105 A61K 31/711 4C086 31/711 39/395 4C206 38/00 45/00 39/395 A61P 35 / 00 45/00 41/00 A61P 35/00 A61B 17/36 350 41/00 A61K 37/02 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB , GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG ), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, A , AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX , NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Joan Smolik United States of America 37774 Lo Udon Tanashicote 119 (72) Inventor Eric A. Wokter United States of America Tennessee 37830 Oak Ridge Bypass Drive 138 (72) Inventor Walter Fisher United States of America Sea State 37931 Knoxville Carl Valentine Road 8514 F-term (Reference) 4C026 AA01 BB08 FF17 4C060 MM24 4C066 AA01 AA07 CC04 LL30 4C084 AA01 AA17 MA65 NA13 NA15 ZB262 ZC802 4C085 AA13 AA01 4A03 MA03 NA03 MA03 NA03 MA05 MA85 NA13 NA14 NA15 ZB26

Claims (67)

[Claims] 1. A method for local treatment of diseased tissue, comprising: applying a PDT drug to the diseased tissue to form a treatment zone; removing excess drug; and applying light to the treatment zone. Activating a drug associated with the tissue, and wherein the light penetrates the treatment zone with minimal activation of the drug outside the treatment zone. 2. The method of claim 1, wherein the light is at a wavelength that penetrates the treatment zone while minimizing further penetration into surrounding tissue. 3. The method of claim 2, wherein said wavelength is between about 400-600 nm. 4. The method of claim 1, wherein said light activates said drug by single photon excitation. 5. The method of claim 1, wherein said light activates said drug by two-photon excitation. 6. The method of claim 1, wherein the steps of applying the PDT agent, removing excess agent, and applying light are repeated one or more times. 7. The method of claim 1, further comprising diagnosing said diseased tissue prior to applying said PDT agent. 8. The method of claim 7, wherein said diagnosing comprises using autofluorescence of said diseased tissue. 9. The method of claim 7, wherein the step of diagnosing comprises detecting selective uptake of the indicator drug. 10. The method of claim 9, wherein said indicator agent is selected from the group consisting of a fluorescent dye and a PDT agent. 11. The step of applying the PDT agent, removing excess agent and applying light substantially immediately after the step of diagnosing, wherein the method of diagnosis and treatment is performed in a single procedure. 9. The method according to claim 7, wherein
the method of. 12. The method of claim 7, wherein there is a delay between said diagnosing and applying a PDT drug. 13. The method of claim 1, wherein said PDT agent is Rose Bengal. 14. The method of claim 1, wherein said light is at a wavelength of about 500-600 nm. 15. The method of claim 1, wherein one or more of said PDT agents is applied to said diseased tissue. 16. The method of claim 1, wherein said PDT comprises a target component. 17. The method according to claim 17, wherein the target component is DNА, RNА, an amino acid, an antibody, a protein, a ligand, a hapten, a carbohydrate receptor or a complex drug, a lipid receptor or a complex drug, a protein receptor or a complex receptor, a chelating agent, 17. The method of claim 16, wherein the method is selected from the group consisting of: and an encapsulated excipient. 18. The method of claim 1, wherein said PDT agent is applied directly to said diseased tissue. 19. The method of claim 1, wherein said PDT agent is applied systemically. 20. The method of claim 1, wherein said excess drug is removed by natural systemic clearance. 21. The method of claim 1, wherein said excess drug is removed by flushing said tissue with a liquid. 22. The method of claim 1, further comprising applying heat to the treatment zone to increase activation of the drug. 23. The method of claim 1, wherein said light is applied via a balloon catheter device. 24. The method of claim 23, wherein said balloon catheter device is non-cooperative. 25. The method of claim 24, wherein the non-cooperative balloon catheter device is expanded to substantially expand the treatment zone. 26. The method of claim 23, wherein said balloon catheter is cooperative. 27. The method of claim 23, wherein said balloon catheter is filled with a scattering medium. 28. The method of claim 23, wherein said balloon catheter includes a material that scatters light. 29. The method of claim 1, wherein said light is applied by direct illumination. 30. The group of light comprising a fiber optic bundle, a hollow core optical waveguide, a liquid filled waveguide, a light emitting diode, a microlaser, a monochromatic laser, a continuous laser, a lamp, a continuous wave laser, and a pulsed laser. The method of claim 1, wherein the method is applied by a more selected light source. 31. A method for treating a disease in a blood vessel of the circulatory system, comprising: applying a PDT agent to diseased tissue in the blood vessel to form a treatment zone; and applying light to the treatment zone. Activating a drug associated with the tissue, wherein the light penetrates the treatment zone with minimal activation of the drug outside the treatment zone. 32. The method of claim 31, wherein said PDT drug is applied parenterally. 33. The method of claim 31, wherein said PDT drug is applied via intravenous injection. 34. The method of claim 31, wherein said light is applied by a fiber catheter. 35. The method of claim 31, wherein said light is at a wavelength of about 400-600 nm. 36. The method of claim 31, wherein said PDT agent is applied directly to diseased tissue. 37. The method of claim 31, wherein said medicament is applied through a capillary. 38. The method of claim 31, wherein said PDT agent is Rose Bengal. 39. The method of claim 31, wherein said light is at a wavelength of about 500-600 nm. 40. An apparatus for local treatment of diseased tissue, comprising: a PDT agent for applying to the diseased tissue to form a treatment zone; a means for removing excess agent; and the treatment zone. A light source that activates the PDT agent in the method, wherein the light source can penetrate the diseased tissue while minimizing activation of the drug outside the diseased tissue. apparatus. 41. The apparatus of claim 40, wherein the light is at a wavelength that penetrates the treatment zone while minimizing further penetration into surrounding tissue. 42. The apparatus of claim 41, wherein said wavelength is between about 400-600 nm. 43. The device of claim 40, wherein said light activates said drug by single photon excitation. 44. The device of claim 40, wherein said light activates said drug by two-photon excitation. 45. The apparatus of claim 40, further comprising an indicator drug for diagnosing the diseased tissue, wherein the indicator drug is diagnosed by detecting selective ingestion of the indicator drug. 46. The apparatus of claim 45, wherein said indicator agent is selected from the group consisting of a fluorescent dye and a PDT agent. 47. The device of claim 40, wherein said PDT drug is Rosengel. 48. The apparatus of claim 47, wherein said light is at a wavelength of about 500-600 nm. 49. The device of claim 40, further comprising one or more PDT agents applied to said diseased tissue. 50. The device of claim 40, wherein said PDT agent comprises a target component. 51. The target component is DNА, RNА, amino acid, antibody, protein, ligand, hapten, carbohydrate receptor or complex drug, lipid receptor or complex drug, protein receptor or complex receptor, chelating agent, 51. The device of claim 50, wherein the device is selected from the group consisting of: and an encapsulated excipient. 52. The device of claim 40, wherein said PDT agent is applied directly to said diseased tissue. 53. The device of claim 40, wherein said PDT agent is applied systemically. 54. The device of claim 40, further comprising heat in addition to the treatment zone to increase activation of the drug. 55. The device of claim 54, wherein said heat is applied by superheated liquid in a balloon catheter device. 56. The apparatus of claim 54, wherein said heat is applied by a transparent heating pad. 57. The device of claim 40, wherein said light is applied via a balloon catheter device. 58. The device of claim 57, wherein said balloon catheter device is non-cooperative. 59. The device of claim 58, wherein the non-cooperative balloon catheter device is expanded to extend substantially into the treatment zone. 60. The device of claim 57, wherein said balloon catheter is cooperative. 61. The device of claim 57, wherein said balloon catheter is filled with a scattering medium. 62. The device of claim 57, wherein the balloon catheter includes a light scattering material. 63. The apparatus of claim 40, wherein said light is applied by direct illumination. 64. The group of light comprising a fiber optic bundle, a hollow core optical waveguide, a liquid-filled waveguide, a light emitting diode, a microlaser, a monochromatic laser, a continuous laser, a lamp, a continuous wave laser, and a pulsed laser. 41. The device of claim 40, wherein the device is applied by a more selected light source. 65. The method of claim 1, wherein said PDT agent is at least one PDT agent. 66. The method of claim 31, wherein said PDT is at least one PDT drug. 67. The device of claim 40, wherein said PDT is at least one PDT drug.